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Low-Dose LSD as a Dopamine Agonist for Parkinson's?

T

thecookiemonster

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Dec 13, 2009
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In light of the use of ergot-derived dopamine agonists for the treatment of Parkinson's allegedly causing adverse cardiac effects, has anyone attempted to do any experiments with LSD? Most of the papers I've read have observed these adverse cardiac effects after treatment with anywhere from 1mg - 5mg DAILY of cabergoline or pergolide (or what seems like a rather massive dose -- 20mg daily of bromocryptine for 5 YEARS).

LSD is a 5HT-2a agonist (among others), correct? Furthermore, with an active dose at the microgram level, chances are these cardiac effects will be ameliorated. Say you gave 25 µg/day...that's probably sub-psychedelic threshold for most people, but it is 40x less than the SMALLEST dose (1mg) of the other drugs that are currently being used.

Anyway, I'm just curious if anybody's ever heard of this being done. It seems like it'd be pretty easy to just get a bunch of mice, some MPTP, treat with low-dose LSD and then take a look at the usual biochemical findings / alpha-synuclein, substantia nigra composition, etc.

There is the issue of tolerance, since recreational LSD users notice that the effects of LSD are diminished if you don't wait a few days in between. However, subthreshold dosing might ameliorate this effect -- if you do, say, 1/4 of the normal dose and the average refractory period is 4 to 5 days, it might not cause excessive serotonin depletion. Maybe supplementation with low-dose 5-HTP could help.

This has the added advantage of the VERY low cost of production of LSD (of course by a legitimate pharmaceutical company). Again, a 25µg dose would cost something like 40x less than the 1mg of bromocryptine.

I'm just a college student at the moment, so I don't have the resources to test any of this out, but I hopefully will in 10 years or so (I'm going for a MD/PhD in neuroscience / psychiatry). Any thoughts on this would be interesting. I couldn't find any studies that had tried this, but I might have overlooked them. Also, I don't mean to be pretentious having my first post in the "Advanced Drug Discussion" forum...I'm young and still learning, so please don't think that I'm trying to be a know-it-all or anything. I'm excited though to find this forum and I hope that I can learn a lot from all of you--you seem like really, really intelligent people.
 
I'm not one of the intelligent ones, which is probably why I'm missing the point as to what this has to do with dopamine agonism.
 
alexson said:
LSD would totally wipe out the migraine-medication market (Imitrex etc.)
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"Serious cardiac events, including some that have been fatal, have occurred following the use of Imitrex Injection or Tablets. Events reported have included coronary artery vasospasm, transient myocardial ischemia, myocardial infarction, ventricular tachycardia, and ventricular fibrillation." (from Wikipedia on Imitrex)

I'm just wondering if the reason that it hasn't been used experimentally is due to it's schedule 1 status or it's psychoactive side effects, or if it simply doesn't work.

You have imitrex:

200px-Sumatriptan.svg.png


LSD:

200px-LSD_Structure.svg.png


and serotonin:

200px-Serotonin_(5-HT).svg.png


I'm assuming (and this is a hugely basic assumption based on no experience with drug design other than reading) that the conserved benzene/cyclobutene(HN) ring in LSD and Imitrex (and this similarity to the structure of dopamine) is what's responsible for some of the effects.

I guess my question could basically be answered by a simple study: does LSD's seemingly greater "potency" include more potent serotonin potentiation (i.e. is a 25µg dose quantitatively equal to a 2mg dose) or something else? And, if it IS more potent, are there studies / why haven't there been studies looking into it's potential use therapeutically?

Without knowing exactly how LSD binds on the 5-HT receptors, it seems like iso-LSD -might- still bind (the isomer relates to the other end of the molecule). I know that iso-LSD is not "psychoactive," but does anyone know if it is completely inactive biologically? Also, what would happen if you put a hydroxyl group on the LSD molecule to further mimic serotonin?
 
/navarone/ said:
When speaking of Ki, the smaller the value, the higher the affinity.
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^shit that makes so much more sense now.


anyway, what is the connection between serotonin and dopamine here? seems like lsd works with 5-ht receptors, so does methylsergide. But the other drugs you mentioned are dopamine agonists. am i missing something?
 
they are testing lsd right now. i dont know if they care about parkinson's or anything though. 55 gallon drums of lsd...
can i tell you were it is?
 
The other drugs are also dopamine agonists, but they are given at much higher doses than LSD. My curiosity was: why is this the case: is it because LSD is actually a more potent dopamine agonist (and is this why it is psychoactive at such low doses), or is it due to something else?

Because I thought maybe you could avoid some of the side effects of these other medications (supposedly some heart problems and other things) if LSD had the same effect and you gave it at sub-psychedelic doses.

It all sort of rests on whether or not the psychoactive response of LSD is due to it's potency as a dopamine agonist (I know it hits a LOT of receptors and we don't even know the precise pathway) or something else. IF it is due to its potency as a dopamine agonist, then it seems to me like it would be a good target for research (especially since in "impromptu" bioassays, it hasn't really caused any lasting health problems that I have read about and has been used successfully for some 40 years at much higher -- 200 to even 6 or 700µg -- doses).
 
This is getting silly. Bromocryptine's only significant monoamine neurotransmitter activity is at D2. That alone makes it a more logical treatment for Parkinson's. As far as mass vs. cost is concerned, you can buy a bucket of ergoloid mesylates for cheap.
 
i was getting caught up in the fact that lsd is much a more potent agonist for 5-ht than DA, so that serotonin effects would likely dominate at any dose. but tolerance does build ridiculously fast. assuming that the tolerance is due to downregulation of 5ht2a and not increased metabolism, maybe the effects on dopamine receptors (and other 5-hts) would come to the forefront. interesting.
 
It's also worth mentioning that Dopamine agonists are crappy treatments for Parkinsons. Hence they use L-Dopa 99x more than they use Bromocriptine.
 
I would take dopamine agonists over L-dopa, merely because 1000mg of L-dopa has about same effect as what, 5mg lisuride?
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And that's why you aren't a doctor.

Dopamine agonists aren't very good treatments. They're generally less effective, have more serious side effects and aren't well taken by patients.

L-Dopa, on the other hand, is generally better received and is more effective. That's why it's used more.

Potency doesn't mean shit if the effect is less positive. Heroin is far less potent than fentanyl, but the former is almost universally preferred.
 
^ I actually wrote a post identical to that, but then I thought, fuck it, and deleted the post. Funny. (though I didn't have the illustrative heroin/fentanyl example) But yes, what Hammilton said.
 
Besides LSD is a receptor whore - it acts at all the serotonogic subtypes dopamine agonist, noradrenergic agonist & even does something with histamine receptors, so it's potential for what would be seen as unpleasant side effects is huge (I'm assuming you'd need substantial amounts to counteract even mild Parkinsons, by which time the strange movements & garbled speech would be nothing to do with a neurological disease! =D)
 
ok i have a question:

where does the fast tolerance come from? do all the 5-ht receptors get downregulated rather quickly?
 
Not all of them.

The 'tollerance' is noticed from repeated consumption, the 5-HT2a receptor is heavily stimulated from LSD and thats is why normally the same dose of LSD doesn't kick in the same the day after or 2 days after.
The body has its own feedback system and when it feels that something is 'too much' it downregulates its receptors.
The tollerance shifts back n a couple of days but repeated use could causea a severe downregulation of some serotonin receptors that last for a long time.
Thats is why LSD should only be taken at least once a week or once every 5 days.
 
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